Reactive oxygen species damage drives cardiac and mitochondrial dysfunction following acute nano-titanium dioxide inhalation exposure

Abstract

Nanotechnology offers innovation in products from cosmetics to drug delivery, leading to increased engineered nanomaterial (ENM) exposure. Unfortunately, health impacts of ENM are not fully realized. Titanium dioxide (TiO₂) is among the most widely produced ENM due to its use in numerous applications. Extrapulmonary effects following pulmonary exposure have been identified and may involve reactive oxygen species (ROS). The goal of this study was to determine the extent of ROS involvement on cardiac function and the mitochondrion following nano-TiO₂ exposure. To address this question, we utilized a transgenic mouse model with overexpression of a novel mitochondrially-targeted antioxidant enzyme (phospholipid hydroperoxide glutathione peroxidase; mPHGPx) which provides protection against oxidative stress to lipid membranes. MPHGPx mice and littermate controls were exposed to nano-TiO₂ aerosols (Evonik, P25) to provide a calculated pulmonary deposition of 11 µg/mouse. Twenty-four hours following exposure, we observed diastolic dysfunction as evidenced by E/A ratios greater than 2 and increased radial strain during diastole in wild-type mice (p < 0.05 for both), indicative of restrictive filling. Overexpression of mPHGPx mitigated the contractile deficits resulting from nano-TiO₂ exposure. To investigate the cellular mechanisms associated with the observed cardiac dysfunction, we focused our attention on the mitochondrion. We observed a significant increase in ROS production (p < 0.05) and decreased mitochondrial respiratory function (p < 0.05) following nano-TiO₂ exposure which were attenuated in mPHGPx transgenic mice. In summary, nano-TiO₂ inhalation exposure is associated with cardiac diastolic dysfunction and mitochondrial functional alterations, which can be mitigated by the overexpression of mPHGPx, suggesting ROS contribution in the development of contractile and bioenergetic dysfunction.

Keywords:

• Mitochondria
• cardiac function
• titanium dioxide
• reactive oxygen species
• antioxidant

Disclosures statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Additional information

Funding

This work was supported by the National Institutes of Health from the National Heart, Lung and Blood Institute [R01 HL128485] awarded to JMH. This work was supported by the National Institutes of Health from the National Institute of Environmental Safety and Health [R01 ES015022] awarded to TRN. This work was supported by an American Heart Association Predoctoral Fellowship (AHA 13PRE16850066) awarded to CEN. This work was supported by a National Science Foundation IGERT: Research and Education in Nanotoxicology at West Virginia University [1144676] awarded to QAH. This work was supported by an American Heart Association Predoctoral Fellowship (AHA 17PRE33660333) awarded to QAH. Ingenuity Pathway Analyses were supported by a WV-INBRE Grant [P20GM103434]. Small animal imaging and image analysis were performed in the West Virginia University Animal Models & Imaging Facility (AMIF), which has been supported by the WVU Cancer Institute and NIH grants P30 GM103488 and S10 RR026378. Proteomic experiments were performed in conjunction with Protea Biosciences. This research was supported by the Intramural Research Program of the NIH, NIEHS (Grants 1ZIAES025045-17 and 1ZIAES049019-21).